1. Field of the Invention
The present invention relates to the field of treating patients having symptoms of microbial infections or sepsis, with the aim to reduce the high mortality and morbidity that results from the septic process.
2. Description of the Background Art
The treatment of severe microbial infection, bacteraemia and sepsis, accompanied by the presence of massive gram-negative and gram-positive bacterials or fungi, i.e. candida spp, including pus, is quite complex and difficult to treat by conventional methods. Those infections include, but are not restricted to, surgical infections, severe abdominal infections such as peritonitis, pancreatitis, gall bladder empyema, pleura empyema, as well as bone infections such as osteomyelitis. In hospitals several situations have been associated with the development of septicaemia, sepsis and septic shock, including use of immuno-suppressants (corticosteroids), chemotherapy, radiation, contaminated i.v. fluids, haemorrhagic shock, ischaemia, trauma, cancer, immuno-deficiency, virus infections, diabetes, various forms of infections from Internal Medicine, and sepsis following nosocomial gram-negative and gram-positive infections.
Many patients develop severe infections while treated with antibiotic therapy. Because conventional powerful broad-spectrum antibiotics rapidly rupture microbial cell walls, administration of antibiotics to critically ill patients with severe microbial infection can endanger the life of the patient. This can occur by massive release of bacterial endo-toxins, which include lipopolysaccharide (LPS) components of the outer membrane of gram-negative bacteria, and are pivotal in triggering sepsis and shock. This is precipitated by the antibiotic attack on the bacterial outer membrane, or disturbing the murein synthesis, protein biosynthesis, or DNA-topology (gyrase-inhibitors)of the organism.
Sepsis also often results from a gram-positive bacterial infection, especially of streptococcus or staphylococcus species, and their exo-toxins. Also, the protein component of the bacterial endotoxins from the bacterial outer membrane (OM) play an important role in the pathogenesis of sepsis. Bacterial translocation, by disruption of the gut barrier, functions by the passage of viable bacteria through the epithelial mucosa and lamina propria of the gastrointestinal tract to the lymph nodes, spleen, liver, peritoneum and blood, thus becoming a further source of endotoxins.
The broad use of antibiotics also significantly influences multiresistance of microorganisms and results in bacterial overgrowth.
The release of toxins, triggered by the action of antibiotics on microbial cells, in the first instance activates the patient's defense mechanisms, i.e. the blood monocytes, leucocytes and macrophages of the patient, mediated by endogenous glycoproteins known as cytokines, in order to protect the patient's body from infection. In patients with symptoms of severe infection, the toxic effects are as follows. The above-noted cytokines progress in overreaction of the host, in a type of cascade, through the release of further cytokines such as TNF-.alpha. (Tumor Necrosis Factor), one of the primary mediators of the septic process, and Interleukins (IL-1.alpha., IL-.beta., IL-6 etc.), resulting in tissue damage from such an excessive release of mediators. Thus, administration of antibiotics leads first to a rise in TNF-a and secondly other cytokines and factors like leukotrienes prostaglandins, thromboxane, PAF (platelet activating factors), and gamma-interferon. If the liberation of toxins (including endotoxins and endotoxins) continues due to the activity of antibiotics on the microbes, an enormous rise in cytokines results in an over-reaction of the patient's defense systems, culminating in sepsis, sepsis syndrome and septic shock (Mediator disease), and subsequent death of the patient by multiorgan failure.
In animal experiments on peritonitis models, with massive bacterial introduction in the abdominal cavity, using mice, rats and rabbits injected, i.e., with pure bacterial cultures of E. coli and Bacteroides fragilis, nearly 100% of infected animals die when using intraperitoneally (i.p.) delivered conventional bactericidal antibiotics and quick-working antiseptics such as povidone-iodine. For example, povidone-iodine leads to a massive release of bacterial toxins. The bacteraemia disappears for a short period of time, but ultimately a massive reinfection takes place whereby the host body's immunity is almost completely destroyed by the release of bacterial toxin, with substantially 100% lethality.
Even in cases where the life of a sepsis patient is initially saved using antibiotics, there exists only a small long-term chance of survival following the occurrence (approximately 3 years), because of the damage caused to the patient's organs (organ failure) by the bacterial toxins.
The compounds Taurolidine (Taurolin .RTM.) and Taurultam are known antimicrobial substances with broad-spectrum activity against aerobic and anaerobic bacteria, mycobacteria and fungi. Unlike antibiotics, these compounds do not result in release of large quantities of bacterial toxins. They have been suggested as a substitute for antibiotics for administration in patients both to combat infections and to deal with sepsis and septic shock.
There remains an urgent need in the art for improved methods of treating patients with severe microbial infections.